USE OF VITAMIN-D ANALOGUES IN THE TREATMENT OF ACNE

Description

[0001] This invention relates to the use of the vitamin D analogue MC 903;
   1S,1'E,3R,5Z,7E,20R)-(9,10)-seco-20-(3'-cyclopropyl-3'-hydroxyprop-1'-enyl)-1,3-dihydroxypregna-5,7,10(19)-triene
in the preparation of a pharmaceutical preparation for the treatment of acne.

[0002] Among the factors contributing to the aetiology of acne, an increased sebum production appears to be of major importance, as the severity of the acne parallels sebum excretion rates.

[0003] In accordance with this, the reduction of sebum production induced by treatment with oestrogens or isotretinoin leads to an improvement in acne. However, the hormonal effects of the former precludes its widespread use, and isotretinoin is teratogenic and is only used for very severe acne due to this and other side effects (Drug and Therapeutics Bulletin, Vol. 22, No. 24, December 3, 1984).

[0004] Recently it has been found that topical application of 1α,25-dihydroxyvitamin D₃ (1α,25-(OH)₂D₃) reduces the size of sebaceous glands in the ear of male Syrian hamsters (V.L. Malloy et al, The tricontinental Meeting for Investigative Dermatology, Washington, USA, 1989).

[0005] However, this observation may be of limited utility in the human medicine because transdermal absorption after topical application of 1α,25-(OH)₂D₃ or systemic treatment with this compound, may, due to its potent calcemic activity, give rise to undesired effects leading to hypercalcemia.

[0006] However, by choosing a vitamin D analogue which has only moderate activity on calcium metabolism compared to 1,25-(OH)₂D₃, but having retained the ability to activate receptors for 1,25-(OH)₂D₃ not associated with calcium absorption or bone calcium mobilization it is possible to treat acne successfully without having the risk of inducing hypercalcemia.

[0007] The vitamin D analogue for use in the present pharmaceutical preparations is a compound described in international patent application No. PCT/DK86/00081, international filing date 14th July, 1986, International Publication No. WO 87/00834 designated MC 903 (example 5 in said patent application) (confer also Calverley, M., Tetrahedron 43, 4609-4619 (1987); Binderup, L. and Bramm, E., Biochemical Pharmacology 37, 889-895 (1988)).

[0008] The mentioned compound shall form part of pharmaceutical preparations, in particular for topical use, which are useful in the treatment of human disorders as described above, such as a liniment, a lotion or a cream which in addition to the vitamin D analogue in question may contain further active ingredients. The concentration of the active ingredient will generally be between 1 and 100 µg/g.

[0009] The formulations will be applied once or twice daily for prolonged periods of time.

[0010] The formulations prepared according to the present invention comprise the active compound in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the preparations and not deleterious to the recipient thereof.

[0011] The preparations may conveniently be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with the carrier which constitutes one or more accessory ingredients. In general, the preparations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired preparation.

[0012] Preparations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.

[0013] In addition to the aforementioned ingredients, the preparations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

[0014] The preparations may, as mentioned above, contain further therapeutically active compounds usually applied in the above mentioned treatment.

[0015] In the topical treatment, ointments, creams, or lotions containing from 1-100 µg/g of the vitamin D analogue or metabolites are administered.

[0016] Preparations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active compound; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active compound may also be administered in the form of a bolus, electuary or paste.

[0017] A tablet may be made by compressing or moulding the active compound optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active compound in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active compound and suitable carrier moistened with an inert liquid diluent.

[0018] Preparations for rectal administration may be in the form of a suppository incorporating the active compound and a carrier such as cocoa butter, or in the form of an enema.

[0019] Preparations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.

[0020] In addition to the aforementioned ingredients, the preparations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

[0021] The oral preparations are formulated, preferably as tablets, capsules, or drops, containing from 0.5-1000 µg of the vitamin D analogue or metabolites, per dosage unit.

[0022] The invention will now be further described in the following non-limiting Examples:

Example 1 Cream Containing MC 903

[0023] In 1 g almond oil was dissolved 1 mg MC 903. To this solution was added 40 g of mineral oil and 20 g of self-emulsifying beeswax. The mixture was heated to liquify. After the addition of 40 ml hot water, the mixture was mixed well. The resulting cream contains approximately 10 µg of MC 903 per gram of cream.

Example 2 Cream containing 50 µg MC 903/g

[0024] 

MC903	50 mg
Cetomacrogol 1000	25 g
Cetostearyl alcohol	75 g
Chloroallylhexaminium chloride	0.5 g
Glycerol	30 g
Disodium hydrogenphosphate	2 g
Sodium dihydrogenphosphate	0.1 g
Liquid paraffin	60 g
Polyoxyethylene stearylether	12 g
White petrolatum	160 g
Purified water up to	1000 g

[0025] Dissolve MC903 in a solution of glycerol, disodium hydrogenphosphate, sodium dihydrogenphosphate and polyoxyethylene stearylether dissolved in water. Mix with the melted cetomacrogol 1000, liquid paraffin, cetostearyl alcohol and white petrolatum. Homogenize the emulsion and cool. Dissolve chloroallylhexaminium chloride in part of the water and mix until homogeneous with the emulsion. Fill the cream in aluminium tubes.

Example 3 Cream containing 100 µg MC 903/g

[0026] 

MC903	100 mg
Cetomacrogol 1000	30 g
Cetostearyl alcohol	60 g
Chloroallylhexaminium chloride	0.5 g
Propylenglycol	30 g
Disodium hydrogenphosphate	2 g
Sodium dihydrogenphosphate	0.1 g
Liquid paraffin	50 g
White petrolatum	170 g
Purified water up to	1000 g

[0027] Melt cetomacrogol 1000, cetostearyl alcohol, liquid paraffin and white petrolatum at 75°C. Dissolve propylenglycol in water at 75°C and mix the solution with the fatty phase. Homogenize the emulsion and cool to 30°C. Mill MC903 to particle size below 5µm and suspend in an aqueous solution of disodium hydrogenphosphate, sodium dihydrogenphosphate and chloroallylhexaminium chloride. Add the suspension to the emulsion and fill the cream in tubes.

Example 4 Lotion containing 50 µg MC 903/g

[0028] 

MC903	50 mg
Absolute alcohol	400 g
Hydroxypropylcellulose	1 g
Menthol	1 g
Sodium citrate	1 g
Propylenglycol	40 g
Purified water up to	1000 ml

[0029] Dissolve hydroxypropylcellulose, sodium citrate and propylenglycol in water. Mix with a solution of MC903 and menthol in absolute alcohol. Fill the lotion in polyethylen plastic bottles.

Example 5 Use of MC 903 lotion in the treatment of acne vulgaris of the face

[0030] A total of 10 patients with acne vulgaris of the face have been assessed in an open, non-controlled study of MC 903 lotion. Patients were treated for up to 6 weeks with twice daily applications of the lotion: 50 µg/ml. The study provided evidence that MC 903 lotion was well tolerated. Furthermore, the data pertaining to the therapeutic efficacy of the lotion are encouraging.

Claims

1. The use of the compound MC 903:
   1S,1'E,3R,5Z,7E,20R)-(9,10)-seco-20-(3'-cyclopropyl-3'-hydroxyprop-1'-enyl)-1,3-dihydroxypregna-5,7,10(19)-triene
in the manufacture of a medicament for the treatment of acne.

2. The use according to claim 1 wherein the medicament is provided for topical application containing the active component as defined in claim 1 in an amount of from 1 to 100 µg/g of the medicament.

3. The use according to claim 1 wherein the medicament is provided for oral application containing the active ingredient as defined in claim 1 in an amount of from 0.5 to 1000 µg per dosage unit.

Ansprüche

1. Verwendung der Verbindung MC 903:
   (1S,1'E,3R,5Z,7E,20R)-(9,10)-Seco-20-(3'-cyclopropyl-3'-hydroxyprop-1'-enyl)-1,3-dihydroxypregna-5,7,10(19)-trien
zur Herstellung eines Medikamentes zur Behandlung von Akne.

2. Verwendung nach Anspruch 1, wobei das Medikament zur topischen Applikation vorgesehen ist und die in Anspruch definierte aktive Komponente in einer Menge von 1 bis 100 µg/g des Medikamentes enthält.

3. Verwendung nach Anspruch 1, wobei das Medikament zur oralen Applikation vorgesehen ist und den in Anspruch 1 definierten aktiven Bestandteil in einer Menge von 0,5 bis 1000 µg pro Dosiseinheit enthält.

Revendications

1. Utilisation du composé MC 903 :
(1S,1'E,3R,5Z,7E,2OR)-(9,10)-seco-20-(3'-cyclopropyl-3'-hydroxyprop-1'-ényl)-1,3-dihydroxyprégna-5,7,10(19)-triène
dans la préparation d'un médicament destiné au traitement de l'acné.

2. Utilisation selon la revendication 1, dans laquelle le médicament est prévu pour une application locale contenant le principe actif tel que défini dans la revendication 1 à raison de 1 à 100 µg/g du médicament.

3. Utilisation selon la revendication 1, dans laquelle le médicament est prévu pour une application orale contenant le principe actif tel que défini dans la revendication 1 à raison de 0,5 à 1000 µg par dose unitaire.